Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension
Year: 2023
Type: article
Abstract: Ligands for the serotonin 2B receptor (5-HT2B) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT2B. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia–induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT2B ligands with high potency and selectivity for the 5-HT2B receptor subtype. Next-generation 5-HT2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug–enabling studies.
Authors: Michael S. Valentine, Aaron M. Bender, Sheila Shay, Krista C. Paffenroth, Santhi Gladson, Jonathan W. Dickerson, Katherine J. Watson, Nicholas J. Kapolka, Olivier Boutaud, Jerri M. Rook, Timothy S. Blackwell, Bryan L. Roth, Fiona E. Harrison, Eric D. Austin, James D. West, Craig W. Lindsley, W. David Merryman
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,530
OpenAlex ID: W4386700162